A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus

Autores
Macedo, Daiana; Brito Devoto, Tomás; Pola, Santiago; Finquelievich, Jorge L.; Cuestas, María Luján; Garcia Effron, Guillermo
Año de publicación
2020
Idioma
inglés
Tipo de recurso
artículo
Estado
versión publicada
Descripción
The treatment of invasive and chronic aspergillosis involves triazole drugs. Its intensive use has resulted in the selection of resistant isolates, and at present, azole resistance in Aspergillus fumigatus is considered an emerging threat to public health worldwide. The aim of this work is to uncover the molecular mechanism implicated in the azole resistance phenotype of three Aspergillus fumigatus clinical strains isolated from an Argentinian cystic fibrosis patient under long-term triazole treatment. Strain susceptibilities were assessed, and CYP51A gene sequences were analyzed. Two of the studied Aspergillus fumigatus strains harbored the TR34- L98H allele. These strains showed high MIC values for all tested triazoles (>16.00μg/ml, 1.00 μg/ml, 1.00 μg/ml, and 2.00 μg/ml for itraconazole, isavuconazole, posaconazole, and voriconazole, respectively). The third strain had a novel amino acid change (R65K) combined with the TR34-L98H mutations. This new mutation combination induces a pan-azole MIC augment compared with TR34-L98H mutants (>16 μg/ml, 4.00μg/ml, 4.00μg/ml, and 8.00μg/ml for itraconazole, isavuconazole, posaconazole, and voriconazole, respectively). The strain harboring the TR34-R65K-L98H allele showed no inhibition halo when voriconazole susceptibility was evaluated by disk diffusion. The effect of these mutations in the azole-resistant phenotype was confirmed by gene replacement experiments. Transformants harboring the TR34-L98H and TR34-R65KL98H alleles mimicked the azole-resistant phenotype of the clinical isolates, while the incorporation of the TR34-R65K and R65K alleles did not significantly increase azole MIC values. This is the first report of the TR34-L98H allele in Argentina. Moreover, a novel CYP51A allele (TR34-R65K-L98H) that induces a pan-azole MIC augment is described.
Fil: Macedo, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina
Fil: Brito Devoto, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Pola, Santiago. Universidad de Buenos Aires; Argentina
Fil: Finquelievich, Jorge L.. Universidad de Buenos Aires; Argentina
Fil: Cuestas, María Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Garcia Effron, Guillermo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina
Materia
ARGENTINA
ASPERGILLUS
AZOLE
CYP51A
MUTATION
RESISTANCE
SOUTH AMERICA
TR34/L98H
Nivel de accesibilidad
acceso abierto
Condiciones de uso
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
Repositorio
CONICET Digital (CONICET)
Institución
Consejo Nacional de Investigaciones Científicas y Técnicas
OAI Identificador
oai:ri.conicet.gov.ar:11336/149634
Acceder
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oai_identifier_str oai:ri.conicet.gov.ar:11336/149634
network_acronym_str CONICETDig
repository_id_str 3498
network_name_str CONICET Digital (CONICET)
spelling A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatusMacedo, DaianaBrito Devoto, TomásPola, SantiagoFinquelievich, Jorge L.Cuestas, María LujánGarcia Effron, GuillermoARGENTINAASPERGILLUSAZOLECYP51AMUTATIONRESISTANCESOUTH AMERICATR34/L98Hhttps://purl.org/becyt/ford/3.3https://purl.org/becyt/ford/3The treatment of invasive and chronic aspergillosis involves triazole drugs. Its intensive use has resulted in the selection of resistant isolates, and at present, azole resistance in Aspergillus fumigatus is considered an emerging threat to public health worldwide. The aim of this work is to uncover the molecular mechanism implicated in the azole resistance phenotype of three Aspergillus fumigatus clinical strains isolated from an Argentinian cystic fibrosis patient under long-term triazole treatment. Strain susceptibilities were assessed, and CYP51A gene sequences were analyzed. Two of the studied Aspergillus fumigatus strains harbored the TR34- L98H allele. These strains showed high MIC values for all tested triazoles (>16.00μg/ml, 1.00 μg/ml, 1.00 μg/ml, and 2.00 μg/ml for itraconazole, isavuconazole, posaconazole, and voriconazole, respectively). The third strain had a novel amino acid change (R65K) combined with the TR34-L98H mutations. This new mutation combination induces a pan-azole MIC augment compared with TR34-L98H mutants (>16 μg/ml, 4.00μg/ml, 4.00μg/ml, and 8.00μg/ml for itraconazole, isavuconazole, posaconazole, and voriconazole, respectively). The strain harboring the TR34-R65K-L98H allele showed no inhibition halo when voriconazole susceptibility was evaluated by disk diffusion. The effect of these mutations in the azole-resistant phenotype was confirmed by gene replacement experiments. Transformants harboring the TR34-L98H and TR34-R65KL98H alleles mimicked the azole-resistant phenotype of the clinical isolates, while the incorporation of the TR34-R65K and R65K alleles did not significantly increase azole MIC values. This is the first report of the TR34-L98H allele in Argentina. Moreover, a novel CYP51A allele (TR34-R65K-L98H) that induces a pan-azole MIC augment is described.Fil: Macedo, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; ArgentinaFil: Brito Devoto, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Pola, Santiago. Universidad de Buenos Aires; ArgentinaFil: Finquelievich, Jorge L.. Universidad de Buenos Aires; ArgentinaFil: Cuestas, María Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; ArgentinaFil: Garcia Effron, Guillermo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; ArgentinaAmerican Society for Microbiology2020-08info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionhttp://purl.org/coar/resource_type/c_6501info:ar-repo/semantics/articuloapplication/pdfapplication/pdfapplication/pdfhttp://hdl.handle.net/11336/149634Macedo, Daiana; Brito Devoto, Tomás; Pola, Santiago; Finquelievich, Jorge L.; Cuestas, María Luján; et al.; A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 64; 8; 8-2020; 1-110066-4804CONICET DigitalCONICETenginfo:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.02501-19info:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/AAC.02501-19info:eu-repo/semantics/openAccesshttps://creativecommons.org/licenses/by-nc-sa/2.5/ar/reponame:CONICET Digital (CONICET)instname:Consejo Nacional de Investigaciones Científicas y Técnicas2025-09-29T10:15:15Zoai:ri.conicet.gov.ar:11336/149634instacron:CONICETInstitucionalhttp://ri.conicet.gov.ar/Organismo científico-tecnológicoNo correspondehttp://ri.conicet.gov.ar/oai/requestdasensio@conicet.gov.ar; lcarlino@conicet.gov.arArgentinaNo correspondeNo correspondeNo correspondeopendoar:34982025-09-29 10:15:15.525CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicasfalse
dc.title.none.fl_str_mv A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus
title A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus
spellingShingle A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus
Macedo, Daiana
ARGENTINA
ASPERGILLUS
AZOLE
CYP51A
MUTATION
RESISTANCE
SOUTH AMERICA
TR34/L98H
title_short A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus
title_full A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus
title_fullStr A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus
title_full_unstemmed A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus
title_sort A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus
dc.creator.none.fl_str_mv Macedo, Daiana
Brito Devoto, Tomás
Pola, Santiago
Finquelievich, Jorge L.
Cuestas, María Luján
Garcia Effron, Guillermo
author Macedo, Daiana
author_facet Macedo, Daiana
Brito Devoto, Tomás
Pola, Santiago
Finquelievich, Jorge L.
Cuestas, María Luján
Garcia Effron, Guillermo
author_role author
author2 Brito Devoto, Tomás
Pola, Santiago
Finquelievich, Jorge L.
Cuestas, María Luján
Garcia Effron, Guillermo
author2_role author
author
author
author
author
dc.subject.none.fl_str_mv ARGENTINA
ASPERGILLUS
AZOLE
CYP51A
MUTATION
RESISTANCE
SOUTH AMERICA
TR34/L98H
topic ARGENTINA
ASPERGILLUS
AZOLE
CYP51A
MUTATION
RESISTANCE
SOUTH AMERICA
TR34/L98H
purl_subject.fl_str_mv https://purl.org/becyt/ford/3.3
https://purl.org/becyt/ford/3
dc.description.none.fl_txt_mv The treatment of invasive and chronic aspergillosis involves triazole drugs. Its intensive use has resulted in the selection of resistant isolates, and at present, azole resistance in Aspergillus fumigatus is considered an emerging threat to public health worldwide. The aim of this work is to uncover the molecular mechanism implicated in the azole resistance phenotype of three Aspergillus fumigatus clinical strains isolated from an Argentinian cystic fibrosis patient under long-term triazole treatment. Strain susceptibilities were assessed, and CYP51A gene sequences were analyzed. Two of the studied Aspergillus fumigatus strains harbored the TR34- L98H allele. These strains showed high MIC values for all tested triazoles (>16.00μg/ml, 1.00 μg/ml, 1.00 μg/ml, and 2.00 μg/ml for itraconazole, isavuconazole, posaconazole, and voriconazole, respectively). The third strain had a novel amino acid change (R65K) combined with the TR34-L98H mutations. This new mutation combination induces a pan-azole MIC augment compared with TR34-L98H mutants (>16 μg/ml, 4.00μg/ml, 4.00μg/ml, and 8.00μg/ml for itraconazole, isavuconazole, posaconazole, and voriconazole, respectively). The strain harboring the TR34-R65K-L98H allele showed no inhibition halo when voriconazole susceptibility was evaluated by disk diffusion. The effect of these mutations in the azole-resistant phenotype was confirmed by gene replacement experiments. Transformants harboring the TR34-L98H and TR34-R65KL98H alleles mimicked the azole-resistant phenotype of the clinical isolates, while the incorporation of the TR34-R65K and R65K alleles did not significantly increase azole MIC values. This is the first report of the TR34-L98H allele in Argentina. Moreover, a novel CYP51A allele (TR34-R65K-L98H) that induces a pan-azole MIC augment is described.
Fil: Macedo, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina
Fil: Brito Devoto, Tomás. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Pola, Santiago. Universidad de Buenos Aires; Argentina
Fil: Finquelievich, Jorge L.. Universidad de Buenos Aires; Argentina
Fil: Cuestas, María Luján. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina
Fil: Garcia Effron, Guillermo. Universidad Nacional del Litoral. Facultad de Bioquímica y Ciencias Biológicas; Argentina
description The treatment of invasive and chronic aspergillosis involves triazole drugs. Its intensive use has resulted in the selection of resistant isolates, and at present, azole resistance in Aspergillus fumigatus is considered an emerging threat to public health worldwide. The aim of this work is to uncover the molecular mechanism implicated in the azole resistance phenotype of three Aspergillus fumigatus clinical strains isolated from an Argentinian cystic fibrosis patient under long-term triazole treatment. Strain susceptibilities were assessed, and CYP51A gene sequences were analyzed. Two of the studied Aspergillus fumigatus strains harbored the TR34- L98H allele. These strains showed high MIC values for all tested triazoles (>16.00μg/ml, 1.00 μg/ml, 1.00 μg/ml, and 2.00 μg/ml for itraconazole, isavuconazole, posaconazole, and voriconazole, respectively). The third strain had a novel amino acid change (R65K) combined with the TR34-L98H mutations. This new mutation combination induces a pan-azole MIC augment compared with TR34-L98H mutants (>16 μg/ml, 4.00μg/ml, 4.00μg/ml, and 8.00μg/ml for itraconazole, isavuconazole, posaconazole, and voriconazole, respectively). The strain harboring the TR34-R65K-L98H allele showed no inhibition halo when voriconazole susceptibility was evaluated by disk diffusion. The effect of these mutations in the azole-resistant phenotype was confirmed by gene replacement experiments. Transformants harboring the TR34-L98H and TR34-R65KL98H alleles mimicked the azole-resistant phenotype of the clinical isolates, while the incorporation of the TR34-R65K and R65K alleles did not significantly increase azole MIC values. This is the first report of the TR34-L98H allele in Argentina. Moreover, a novel CYP51A allele (TR34-R65K-L98H) that induces a pan-azole MIC augment is described.
publishDate 2020
dc.date.none.fl_str_mv 2020-08
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
http://purl.org/coar/resource_type/c_6501
info:ar-repo/semantics/articulo
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/11336/149634
Macedo, Daiana; Brito Devoto, Tomás; Pola, Santiago; Finquelievich, Jorge L.; Cuestas, María Luján; et al.; A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 64; 8; 8-2020; 1-11
0066-4804
CONICET Digital
CONICET
url http://hdl.handle.net/11336/149634
identifier_str_mv Macedo, Daiana; Brito Devoto, Tomás; Pola, Santiago; Finquelievich, Jorge L.; Cuestas, María Luján; et al.; A novel combination of CYP51A mutations confers pan-azole resistance in aspergillus fumigatus; American Society for Microbiology; Antimicrobial Agents and Chemotherapy; 64; 8; 8-2020; 1-11
0066-4804
CONICET Digital
CONICET
dc.language.none.fl_str_mv eng
language eng
dc.relation.none.fl_str_mv info:eu-repo/semantics/altIdentifier/doi/10.1128/AAC.02501-19
info:eu-repo/semantics/altIdentifier/url/https://journals.asm.org/doi/10.1128/AAC.02501-19
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
eu_rights_str_mv openAccess
rights_invalid_str_mv https://creativecommons.org/licenses/by-nc-sa/2.5/ar/
dc.format.none.fl_str_mv application/pdf
application/pdf
application/pdf
dc.publisher.none.fl_str_mv American Society for Microbiology
publisher.none.fl_str_mv American Society for Microbiology
dc.source.none.fl_str_mv reponame:CONICET Digital (CONICET)
instname:Consejo Nacional de Investigaciones Científicas y Técnicas
reponame_str CONICET Digital (CONICET)
collection CONICET Digital (CONICET)
instname_str Consejo Nacional de Investigaciones Científicas y Técnicas
repository.name.fl_str_mv CONICET Digital (CONICET) - Consejo Nacional de Investigaciones Científicas y Técnicas
repository.mail.fl_str_mv dasensio@conicet.gov.ar; lcarlino@conicet.gov.ar
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score 13.070432

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